Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
848
result(s) for
"Meredith, David M."
Sort by:
Distribution of copy number alterations and impact of chromosome arm call thresholds for meningioma
Chromosome-arm copy number alterations (CNAs) are an important component of cancer molecular classifiers. CNAs are often translated into binary chromosome arm calls (arm gain/loss) using an arm call threshold before integration into classification schemes. However, substantial variability exists in thresholds used to define arm calls from CNA data. Here, we analyze 1042 meningiomas with whole-genome microarray data and 13 meningiomas with multifocal sampling to characterize how CNA thresholds influence molecular classification and prognostication. Changing arm call thresholds shifts the association of chromosomal arm calls with meningioma recurrence in an arm-dependent manner and upgrades 21.5% of cases from low-grade to high-grade in a molecularly Integrated Grade (IG) scheme. The impact of threshold differences in IG prediction of recurrence is most evident amongst intermediate grade (IG-2) tumors and CNA call thresholds approaching whole-chromosome arm length (>95%). The designation of chromosome loss or gain remains stable across a majority of thresholds, although this varies in a chromosome-dependent manner. CNAs fluctuate among paired primary-recurrent tumors, mostly growing on recurrence, but cluster in discrete sizes within a tumor. Appreciation of the impact of chromosome arm call thresholds can help ensure robustness of molecular classification paradigms.
Defining clinically meaningful criteria for copy number alterations (CNA) remains challenging. Here, the authors explore the distribution and prognostic impact of CNA features in a large clinically annotated cohort of meningiomas, determining arm call thresholds that enable consistent molecular classification and patient stratification.
Journal Article
Molecular and clinicopathologic features of gliomas harboring NTRK fusions
Fusions involving neurotrophic tyrosine receptor kinase (
NTRK
) genes are detected in ≤2% of gliomas and can promote gliomagenesis. The remarkable therapeutic efficacy of TRK inhibitors, which are among the first Food and Drug Administration-approved targeted therapies for
NTRK
-fused gliomas, has generated significant clinical interest in characterizing these tumors. In this multi-institutional retrospective study of 42 gliomas with
NTRK
fusions, next generation DNA sequencing (
n
= 41), next generation RNA sequencing (
n
= 1), RNA-sequencing fusion panel (
n
= 16), methylation profile analysis (
n
= 18), and histologic evaluation (
n
= 42) were performed. All infantile
NTRK
-fused gliomas (
n
= 7) had high-grade histology and, with one exception, no other significant genetic alterations. Pediatric
NTRK
-fused gliomas (
n
= 13) typically involved
NTRK2
, ranged from low- to high-histologic grade, and demonstrated histologic overlap with desmoplastic infantile ganglioglioma, pilocytic astrocytoma, ganglioglioma, and glioblastoma, among other entities, but they rarely matched with high confidence to known methylation class families or with each other; alterations involving
ATRX
,
PTEN
, and
CDKN2A/2B
were present in a subset of cases. Adult
NTRK
-fused gliomas (
n
= 22) typically involved
NTRK1
and had predominantly high-grade histology; genetic alterations involving
IDH1
,
ATRX
,
TP53
,
PTEN
,
TERT
promoter,
RB1
,
CDKN2A/2B
,
NF1
, and polysomy 7 were common. Unsupervised principal component analysis of methylation profiles demonstrated no obvious grouping by histologic grade,
NTRK
gene involved, or age group. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, MAPK, and other pathways. In summary, the study highlights the clinical, histologic, and molecular heterogeneity of
NTRK
-fused gliomas, particularly when stratified by age group.
Journal Article
Characterization of molecular signatures of supratentorial ependymomas
Ependymomas show poor correlation between World Health Organization grade and clinical outcome. A subgroup of supratentorial ependymomas are characterized by
C11orf95-RELA
fusions, presumed to be secondary to chromothripsis of chromosome 11, resulting in constitutive activation of the NF-κB signaling pathway and overexpression of cyclin D1, p65, and L1 cell adhesion molecule (L1CAM). These
RELA
-fused ependymomas are recognized as a separate, molecularly defined World Health Organization entity and might be associated with poor clinical outcome. In this study, we show that immunohistochemistry for NF-κB signaling components, such as L1CAM, p65, and cyclin D1, can help distinguish
RELA
-fused from non-
RELA
-fused supratentorial ependymomas. Furthermore, these three markers can reliably differentiate
RELA
-fused ependymomas from a variety of histologic mimics. Lastly, we report that
RELA
-fused ependymomas may be associated with different chromosomal copy number changes and molecular alterations compared to their non-
RELA
-fused counterparts, providing additional insight into the genetic pathogenesis of these tumors and potential targets for directed therapies.
Journal Article
Embryonal and non‐meningothelial mesenchymal tumors of the central nervous system – Advances in diagnosis and prognostication
The 5th edition of the WHO Classification of Tumours of the Central Nervous System introduces new entities, and provides updated guidance regarding the diagnostic criteria for tumors of the central nervous system (CNS). CNS embryonal tumors and CNS non‐meningothelial mesenchymal tumors can be challenging for practicing pathologists, as the histologic features are not always specific to a particular entity, and integration of microscopic and molecular findings is necessary. This review on CNS embryonal and non‐meningothelial mesenchymal tumors is meant to provide an update with a focus on WHO changes and additions and on recent discoveries with diagnostic, prognostic, and therapeutic implications. A concise review of the CNS embryonal and mesenchymal non‐meningothelial tumors, comprising the most current available information with clinical implications.
Journal Article
Mechanisms and therapeutic implications of hypermutation in gliomas
A high tumour mutational burden (hypermutation) is observed in some gliomas
1
–
5
; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.
Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.
Journal Article
H3K27-altered diffuse midline gliomas with MAPK pathway alterations: Prognostic and therapeutic implications
Large-scale sequencing led to the identification of driver molecular alterations such as FGFR1 and BRAF in occasional diffuse midline gliomas (DMGs) H3K27-mutant but their significance has not been completely explored. We evaluated these associations in our institutional cohorts. We searched our archives for H3K2M7-mutant gliomas and analyzed the co-occurring genetic alterations. The demographics, clinical information, and pathology were reviewed. Oncoplots and Kaplan-Meier survival curves were generated with the maftools R package. We identified 81 patients (age range 2–68, median 26), of which 79 (97%) were DMGs, and 2 were glioneuronal tumors. The 2 glioneuronal tumors (1 with BRAF fusion and 1 BRAF-V600E-mutant) were removed from the outcome analysis. Four cases had BRAF V600E mutation, 12 had FGFR1 hotspot mutations, and one each had KRAS and NRAS pathogenic mutations. The most common correlating anatomic location was the brainstem for the BRAF group and thalamus for the FGFR1group. Follow-up ranged from 0 to 78 months, average 20.4 months. The overall survival in FGFR1- and BRAF V600E-mutant DMGs was not statistically improved when compared with those that were wildtype. However, the possibility of targeted therapy argues for comprehensive sequencing of H3K27-altered gliomas.
Journal Article
SMARCE1 deficiency generates a targetable mSWI/SNF dependency in clear cell meningioma
Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes establish and maintain chromatin accessibility and gene expression, and are frequently perturbed in cancer. Clear cell meningioma (CCM), an aggressive tumor of the central nervous system, is uniformly driven by loss of SMARCE1, an integral subunit of the mSWI/SNF core. Here, we identify a structural role for SMARCE1 in selectively stabilizing the canonical BAF (cBAF) complex core–ATPase module interaction. In CCM, cBAF complexes fail to stabilize on chromatin, reducing enhancer accessibility, and residual core module components increase the formation of BRD9-containing non-canonical BAF (ncBAF) complexes. Combined attenuation of cBAF function and increased ncBAF complex activity generates the CCM-specific gene expression signature, which is distinct from that of NF2-mutated meningiomas. Importantly, SMARCE1-deficient cells exhibit heightened sensitivity to small-molecule inhibition of ncBAF complexes. These data inform the function of a previously elusive SWI/SNF subunit and suggest potential therapeutic approaches for intractable SMARCE1-deficient CCM tumors.
SMARCE1 loss destabilizes the canonical BAF complex and increases the formation of BRD9-containing non-canonical (ncBAF) complexes. SMARCE1-deficient cells, which are a model for clear cell meningioma, are sensitive to ncBAF complex inhibition.
Journal Article
Recurrent EP300-BCOR Fusions in Pediatric Gliomas With Distinct Clinicopathologic Features
Abstract
BCOR is an epigenetic regulator and is genetically altered by mutation, deletion, or gene fusion in a range of cancers. “Central nervous system high-grade neuroepithelial tumor with BCOR alteration” is a recently described entity with characteristic internal tandem duplications within exon 15 of the BCOR gene (hereafter: CNS HGNET-BCOR ex15 ITD). In this case series of 3 patients, we report the clinicopathologic, molecular, and methylome features of gliomas with novel EP300-BCOR in-frame gene fusions, thus expanding the spectrum of BCOR alterations seen in CNS tumors. The gliomas in this series arise in children (ages 10–18), involve the supratentorial compartment, and have an infiltrative pattern of growth and a myxoid/microcystic background with frequent psammomatous calcifications and prominent chicken-wire vessels. All 3 cases had areas with low-grade morphology and 2 of them demonstrated histologic high-grade transformation. In contrast to CNS HGNET-BCOR ex15 ITD, they lack perivascular pseudorosettes. On a t-Distributed Stochastic Neighbor Embedding plot they cluster perfectly together, away from CNS HGNET-BCOR ex15ITD, consistent with a different entity. Gliomas with EP300-BCOR fusions and high-grade histology can demonstrate relatively rapid regrowth after debulking or subtotal resection.
Journal Article
Molecular Alterations in Pediatric Low-Grade Gliomas That Led to Death
Abstract
Pediatric low-grade gliomas (PLGGs) have excellent long-term survival, but death can occasionally occur. We reviewed all PLGG-related deaths between 1975 and 2019 at our institution: 48 patients were identified; clinical data and histology were reviewed; targeted exome sequencing was performed on available material. The median age at diagnosis was 5.2 years (0.4–23.4 years), at death was 13.0 years (1.9–43.2 years), and the overall survival was 7.2 years (0.0–33.3 years). Tumors were located throughout CNS, but predominantly in the diencephalon. Diagnoses included low-grade glioma, not otherwise specified (n = 25), pilocytic astrocytoma (n = 15), diffuse astrocytoma (n = 3), ganglioglioma (n = 3), and pilomyxoid astrocytoma (n = 2). Recurrence occurred in 42/48 cases, whereas progression occurred in 10. The cause of death was direct tumor involvement in 31/48 cases. Recurrent drivers included KIAA1549-BRAF (n = 13), BRAF(V600E) (n = 3), NF1 mutation (n = 3), EGFR mutation (n = 3), and FGFR1-TACC1 fusion (n = 2). Single cases were identified with IDH1(R132H), FGFR1(K656E), FGFR1 ITD, FGFR3 gain, PDGFRA amplification, and mismatch repair alteration. CDKN2A/B, CDKN2C, and PTEN loss was recurrent. Patients who received only chemotherapy had worse survival compared with patients who received radiation and chemotherapy. This study demonstrates that PLGG that led to death have diverse molecular characteristics. Location and co-occurring molecular alterations with malignant potential can predict poor outcomes.
Journal Article